The main objective of this research is to understand the mechanism of action of morphine and related narcotic analgesics, with special reference to the mechanisms by which they produce tolerance and physical dependence. The development of physical dependence is regarded as an important reason for human addiction to these drugs. We have confirmed the finding that morphine inhibits the prostaglandin stimulation of cyclic AMP accumulation in a cultured neuroblastomaglioma hybrid cell line. Although we have not been able to find a consistent effect of morphine on adenylyl cyclase activity in whole brain homogenates, some of the results obtained in the course of this research have led to a better understanding of neurotransmitter stimulation of brain adenylyl cyclase. Another approach to this problem has involved a study of the hyperthermic effects of morphine in cats. Our results strongly suggest that the hyperthermic response results at least in part from a mechanism requiring prostaglandin synthesis. Through a combination of these three approaches, i.e., cell culture studies, studies of morphine induced hyperthermia, and studies of neurotransmitter stimulation of brain adenylyl cyclase, we hope to gain insights that will ultimately contribute to a more complete understanding of morphine action. BIBLIOGRAPHIC REFERENCES: Van Inwegen, R.G., G.A. Robison, W.J. Thompson, K.J. Armstrong, and J.E. Stouffer (1975). Cyclic nucleotide phosphodiesterases and thyroid hormones. J. Biol. Chem. 250: 2452-2456. Van Inwegen, R.C., S.J. Strada and G.A. Robison (1975). Effects of prostaglandins and morphine on brain adenylyl cyclase. Life Sciences 16:1875-1876.